Chronic hepatitis B viral infection (HBV) is an enormous global health concern. Approximately 200 million individuals world wide may be chronically infected with HBV. These infected individuals represent a catastrophic health risk individually, but further represent a major threat of infectivity and magnification of this global epidemic. In the United States 0.1 to 0.5% of all normal, healthy blood donors are hepatitis B surface antigen (HBsAG) positive .sup.1. In a selected population of individuals at high risk for infection (health care professionals, hemophiliacs, hemodialysis patients, and needle-using drug addicts), the percentage of HBsAg positivity may be as high as 30 percent. Chronic HBV carriers may transmit infection by blood contact or sexual contact. Some HBV carriers are of special concern, especially dentists, physicians, or other health care professionals, which have been documented to spread infection to multiple patient contacts.
Hepatitis B viral infection, typically self limited, can result in a chronic infective state. Ten percent of all HBV infections may result in a chronic viral infection, including: (1) chronic persistent infection and, (2) chronic active infection. The former (chronic persistent infection) often renders the patient asymptomatic or mildly symptomatic but still infectious. The latter (chronic active infection) carries a significant risk of severe debilitation as well as life-threatening manifestations such as cirrhosis, portal hypertension, and death. Hepatocellular carcinoma is also strongly correlated with chronic HBV infection.sup.2-4. Symptoms experienced by patients with chronic HBV infection vary from none to mild degrees of fatigue, malaise, myalgia, arthralgia, and pruritis to more severe manifestations of liver dysfunction (such as bleeding disorders, ascites, and encephalopathy). Biochemical abnormalities associated with chronic HBV include an elevation of liver transaminases in the serum, a reduction in serum albumin, elevation of serum bilirubin and prolongation of the prothrombin time (in advanced end-stage liver disease). Hepatitis viruses may be transmitted by human fluids, feces, sexual contact, etc.
Persistent elevation of HBsAg historically has been used as a marker for chronic HBV infection, in conjunction with other pertinent serologic markers. Traditional serologic tests are qualitative; HBsAg titers do not correlate with severity of infection and do not necessarily imply infectivity. In recent years, a hybridization assay with radiolabeled cDNA against HBsAg-DNA (HBV-DNA) has been devised. Direct assay of HBV-DNA allows increased specificity (false positive HBsAg can occur infrequently) and vastly increased sensitivity in detecting HBV infection. Traditional HBV-DNA assay is semiquantitative; slot-blot hybridization with radiolabeled probe cDNA against a serum sample from an infected host can yield an autoradiogram that can be scanned by densitometry to yield an estimate of sample signal intensity which is then correlated to an approximate quantity of HBV-DNA.
Alternatively, a solution hybridization assay using an I.sup.125 labelled cDNA probe of digested samples have been devised by Abbott Labs., Chicago, IL..sup.5. This assay utilizes fluid phase hybridization, single step column chromatography and direct quantitation of HBV-DNA by gamma-emission. The limit of detection is said to be 1.5 picogram HBV-DNA/ml sera.
Effective therapy for HBV infection is important for at least three reasons:
1. Improvement in liver disease in patients with chronic active hepatitis: It has been shown that loss of hepatitis B viral particles (HBeAg and HBV-DNA) accompanying treatment with antivirals has been associated with improvement in histologic liver disease and decrease in levels of serum markers of liver inflammation.sup.6.
2. Loss of infectivity in patients with chronic persistent and chronic active hepatitis: It has been shown that loss of DNA polymerase and HBeAg from sera is accompanied by loss of infectivity of patient sera for susceptible chimpanzees.sup.7.
3. Decreased probability of hepatocellular carcinoma: Strongly supported for the first time by experiments I have performed herein.
Prior to this invention, there was no known treatment for chronic HBV infection and its associated disease. Recent reports have suggested interferon to be of transient benefit in treatment of some patients. Still, upwards of 75% of patients with chronic HBV infection fail to respond to interferon and sustained responses after cessation of interferon treatment are yet less frequent. Other forms of therapy are less efficacious and associated with frequent, undesirable toxic effects (i.e., adenosine arabinoside).